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Data from Th17 Cells Secrete TWEAK to Trigger Epithelial–Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis

Version 2 2024-04-15, 18:21
Version 1 2024-04-15, 07:22
Posted on 2024-04-15 - 07:22
Abstract

Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial–mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK–Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle–encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.

Significance:

TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK–Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.

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FUNDING

Science and Technology Innovation 2030 Major Projects

National Natural Science Foundation of China (NSFC)

Guangdong Basic and Applied Basic Research Foundation

Guangdong Pearl River Program

Guangdong Provincial Natural Science Foundation

The Key Science and Technology Program of Guangzhou

Kelin Outstanding Young Scientist of the First Affiliated Hospital of Sun Yat-sen University

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AUTHORS (27)

Xin Liu
Xin Wang
Qingxia Yang
Li Luo
Ziqin Liu
Xiaoxue Ren
Kai Lei
Shangru Li
Zonglin Xie
Gaomin Zheng
Yifan Zhang
Yijie Hao
Qianying Zhou
Yingdong Hou
Fei Fang
Wu Song
Ji Cui
Jinping Ma
Wenxuan Xie
Shunli Shen
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